Alkyl thio substituted amino benzoic acid alkamine esters and salts thereof



UNITED Patented June 8, 1943 ALKYL THIO SUBSTITUTED AMINO BENZOIC ACllD ALKAMINE ESTERS AND SALTS THEREOF TENT OFFICE,

Kansas City, Mo., a corporation of Delaware N Drawing. Application July 1, 1939, Serial No. 282,352

Claims.

This invention relates to the newly discovered group of organic compounds which have a local anaesthetic action similar to cocaine or procaine, and the like. This application is a continuation in part of the copending application, Serial No.

well known anaesthetics. cifically relates to the products.

expressed algebraically as follows:

5 107,747, filed October 26, 1936, and entitled, after. One specific compound or example herein Alkyl thio-substituted benzoic acid alkamine disclosed is as follows: ester salts, intermediates and process of prepar- The formula of this subsequent specific dising same, allowed January 4, 1939, now Patent closure is set forth as follows for one compound No. 2,173,827, dated September 26, 1939. of one series of compounds:

The chief object of this invention is to prepare a compound which has local anaesthetic proper- (FOOCHZCHZMCIHQKMM esters) ties and which has a toxicity lower than or comparable to that of cocaine, or the like, and which 302115 has anaesthetic properties comparable to tha of cocaine or procaine, or the like.

The compounds hereinafter mentioned have anaesthetic propertiesv comparable to the two beforementioned well known local anaesthetics I the series of compoundswhich' includes the and are less toxic than the beforementioned two above diagrammed compound, the

This invention spe- COOCH2CH2N(C2H5) 2 The products may have the gamer formula may vary in position and SC2H5 may vary in position relativeto each other and the position of R SCSHMNHQCOOQCEHQAIR R NHz. Also in place of (CzHs) wherever the same 15 t alkyl R 15 at} alkyl ladmal and appears other alkyl groups may be substituted R' is an alkyl radical and a: is an integer greater therefon than cirtam mstances R" and R One example of the species group represented may be combined in the form of a polymethylene by the preceding diagram is:

chain; for example, the group NR"R"' may be the piperidyl radical.

' Broadly speaking, the product is an ester of an aromatic acid and an amino alcohol, or is a salt thereof.

Inasmuch as the aforementioned application, now Patent No. 2,173,827, fully and completely sets forth in considerable detail the highly desirable characteristics of the general class of products to which that disclosure and the instant disclosure is directed, no further mention, description or explanation is believed necessary.

It is, however, to be understood that the following specific disclosure is intended to be one of a subgeneric class disclosure as will be quite evident and fully apparent to any qualified chemist having the necessary technical background and experience. For that reason, the inclusion of other than the hereinafter recited examples has intentionally been omitted from the subsequent instant disclosure since in the copending application, now Patent No. 2,173,827, several examples were set forth to illustrate the species distinctions. All of the examples in the aforesaid disclosure relate to one subgeneric form of the broad class of which the instant invention is an example of the subgeneric division as well as several species thereof. For that reason, therefore, specific examples other than the ones given herein of species examples of this subgeneric class, have intentionally been omitted herein- DIETHYLAMINOETHANOL ESTER OF PARA-AMINO- ORTHO-ETHYLTHIOBENZOIC Acn) Para-nitro-ortho-aminobenzoic acid is prepared according to known methods. 9 grams of this acid are boiled with 25 cc. of concentrated hydrochloric acid diluted with 25 cc. of water. This converts the bright red acid to the yellow hydrochloride which does not dissolve completely but remains suspended in the solution. The miX-' ture is then cooled in ice or the like to 0 C., and a solution of 3.6 grams of sodium nitrite in 10 cc. of water is added slowly. Throughout the addition, the temperature is maintained below 1 C. Vigorous stirring'is maintained for 5 minutes after the addition is complete to insure complete diazotization.

The cold diazonium salt solution thus obtained is poured into a well stirred solution of 7.5 grams of potassium ethyl xanthate and 19 grams of sodium carbonate in 100 cc. of water heated to Stirring is continued until the evolution of gases ceases.

, A solution of 6 grams of sodium hydroxide in 25 cc. of water, and 7.5 grams of diethyl sulphate are added to the cold reaction mixture. The solution is refluxed for hours to complete alkylation.

When concentrated hydrochloric acid is added to this cold mixture, para-nitro-ortho-ethylthiobenzoic acid separates out. This product is dissolved in sodium hydroxide solution for neutralization and reprecipitated to remove some of the impurities present. The product, para-nitroortho-ethylthiobenzoic acid,.is finallypurified by crystallization from dilute acetic acid. By titration, the molecular weight was found to be 227, while the calculated molecular weight. is 223. The calculated percentage of" nitrogen therein is 6.l6%, whereas that found-by analysis was 6 /2 grams of the above para-nitro-ortho-ethylthiobenzoic acid is then mixed with 5.6 grams of phosphorus pentachloride in a flask fitted to a reflux condenser. 5 cc. of phosphorus oxychloride is added and after the initial violence of the reaction subsides, the mixture is refluxed for- /2 hr. After removal of the phosphorus oxychloride under reduced pressure, the residue is taken up in boiling chloroform. The chloroform then is distilled off. The product, para-nitro-orthoethylthiobenzoyl chloride, is then recrystallized from high boiling (80-100) petroleum ether.

Para-nitro-ortho-ethylthiobenzoyl chloridewas found to melt at 107 C. The calculated percentage of nitrogen in'thisproduct was 5.74% and that found by analysis was 5.47%.

To a solution of 3.5 grams of diethylaminoethanol in 50 cc. of dry xylene is added exactly 0.69 gram of sodium. The mixture is heated under reflux until all the sodium has dissolved. To this resulting sodium alcoholate solution is added 7.35 grams of the last mentioned acid chloride dissolved in a small amount of dry xylene. This mixture is refluxed for 2 hrs. When the filterd solution is treated with a slow current of dry hydrogen chloride, there separates therefrom, as a gummy mass, the hydrochloride of diethylaminoethyl para-nitro ortho ethylthiobenzoate. The crude'salt was purified by crystallization from dry acetone; have a melting pointof 150 C. The calculated nitrogen percentage in such comp'ound was 7.43%.

tion is filtered after standing until theplatinum coagulates, and the alcohol'is removed under diminished pressure. with dry acetone toremoveany unchanged material. The product is then recrystallized-from absolute alcohol. The hydrochloride of diethylarminoethyl para-amino-ortho-ethylthiobenzoate thus obtained was found to melt at 163 C. The percentage of nitrogen found in this product was 8.34%. nitrogen was 8.41%.

The free base, diethylaminoethyl para-aminoortho-ethylthiobenzoate, may be obtained as an oily liquid by adding alkali to an aqueous solution of the hydrochloride. v

These products, diethylaminoethyl paraamino-ortho-ethylthiobenzoate and its hydrochloride, mentioned hereinbefore, upon'test" have been determined to have suitable anaesthetic power comparable to procaine and cocaine, and

The residue is'then boiled The calculated percentage of to have less toxicity than these two last mentioned products.

A second broad example is the dialkylaminoalkyl esters of various 3-amino-4-alkylthiobenzoic acids. As representatives of this type, there have been prepared the beta-diethylaminoethyl esters of 3-amino-4-methylthiobenzoic, 3- amino-4-ethylthiobenzoic and 3-amino-4-n-propylthiobenzoic acids and the gamma-diethylaminopropyl esters of the two first mentioned acids.

A convenient method of preparing compounds of this type depends on the discovery that the chlorine atom of derivatives of 3-nitro-4-chl0robenzoic acid such as its salts, esters and amides, can readily be replaced by an alkylthio group by treatment with a metal mercaptide, the products being the corresponding derivatives of 3-nitro-4- alkylthiobenzoic acids. Subsequently the nitro group may be converted to an amino group by treatment with a reducing agent andv the acid derivative group converted to the desired ester group by known procedures, with the provision that in these later processes conditions known to be damaging to the alkylthio group, such as excessive alkalinity, should be avoided. Reduction of the nitro group to an amino group has been successfully accomplished with avariety of agents known to be capable of producingthis transformation in other instances anda preferredmethod has been indicatedlin. theexamples hereinafter set forth. Experimentation with a number of known procedures for producing the desired ester grouping has, disclosed; certain successful examples and oneof those found. to be the most convenient is set forth.

Method A solution of the sodium salt'of 3-nitro-lchlorobenzoic acid' was prepared by adding 10 grams ofv sodium bicarbonate and'24.'5 grams of 3-nitro-4-chlorobenzoic acid to a mixtureof 180 cc. of alcoholand 180. cc. of water. This solution was heated to'boiling and mixed with a boiling solution of sodium'methyl mercaptide, prepared by bubbling 12 grams of methyl mercaptan slowly into a solution of 4.8 grams of sodium hydroxide'in' a mixture of'36 cc. of water and 360cc. of 95% alcohol.

The mixture of these two solutions" was boiled for one hour under reflux. The solvent was then removed by distillation under reducedpressure, and the residue, consistingof sodium chloride and the sodium salt of 3-nitro-4-methylthiobenzoic acid, was dissolved in the smallest possible amount of warm water. The resulting solution was acidified with concentrated hydrochloric acid, and the 3-nitro-4-methylthiobenzoic acid which precipitated was filtered from the solution after thorough cooling. Afterpurification by recrystallization from 95% alcohol, this acid was obtained as'a lightyellow solid which melted at 240 C.

Ten grams of 3-nitro-4-rnethylthiobenzoic acid was added to 75cc. of thionyl chloride and the mixture was boiled under reflux; whereupon the acid gradually 'dissolvedi Boiling was continued for thirty minutes after-the solution had become clear and the excess thionyl' chloride was then removed by distillation under diminished pressure, The solid remaining was recrystallized from high-boiling petroleum ether; and" pure 3.- nitro-4-methylthiobenzoyl chloride'was obtained. This substance consists of long, yellow needles which melt at 111 C.

A mixture of 3-nitro-4-methylthiobenzoyl chloride and enough methyl alcohol to maintain a clear solution was boiled under reflux until evolution of hydrogen chloride ceased. The solution was then cooled, whereupon crystals of the methyl ester of 3-nitro-4-methylthiobenzoic acid separated. This ester is a bright yellow solid which melts at 117 C.

Twenty-five grams of the pure methyl ester of 3-nitro-4-methylthiobenzoic acid and 2.5 grams of platinum oxide catalyst (Adams) were suspended in 250 cc. of alcohol and shaken with hydrogen under a pressure of pounds until no further action occurred. The platinum catalyst was filtered from the solution and the alcohol was removed by distillation on the steam bath. The oily residue was then distilled under reduced pressure, and the methyl ester of 3-amino-4-methylthiobenzoic acid was obtained as a clear yellow oil, which distilled at 170 C. at a pressure of 4 mm. and gradually solidified at room temperature. After purification by recrystallizing from alcohol, the ester consists of white, feathery needles which melt at 61 C.

A mixture of eight grams of the methyl ester of 3-amino-4-methylthiobenzoic acid and cc. of beta-diethylaminoethanol was added to 5 cc. of beta-diethylaminoethanol saturated with dry hydrogen chloride. The mixture was heated under reflux at a temperature of 170-l75 C. for 125 hours, after which the excess beta-diethylaminoethanol was removed by distillation under diminished pressure and the residual oil, containing the final product, beta-diethylaminoethyl ester of 3-amino-4-methylthiobenzoic acid, 1

in an impure state was neutralized with cold sodium bicarbonate solution. The resulting mixture was extracted several times with ether, and the ether extracts were dried and distilled under diminished pressure. The relatively pure betadiethylaminoethyl ester of 3-amino-4-methylthiobenzoic acid was obtained as a viscous, yellow oil which distilled at 218 C. under 5 mm. pressure.

The monohydrochloride of this ester was prepared by dissolving the ester in dry ether and adding about 1.25 molecular proportions of dry hydrogen chloride dissolved in dry ether. The monohydrochloride of this ester separated as a fiocculent precipitate. After recrystallization from absolute ethyl alcohol, this monohydrochloride of this ester consists of a white crystalline powder which melts at 168-72 C.

The ethylthio and n-propylthio homologs have been prepared in a similar manner using ethyl mercaptan and n-propyl mercaptan, respectively, in place of methyl mercaptan and as outlined initially herein for the production of the named ester and its hydrochloride. The products obtained in the difierent steps of these two procedures have the following physical constants: 3-nitro-4-ethylthiobenzoic acid, M. P. 231 (3.; 3-nitro-4-n-propylthiobenzoic acid, M. P. 234 0.; the corresponding chlorides, M. P. 102 C., and 94 C., respectively; the methyl esters, M. P.

C. and 97 C., respectively; the methyl ester of 3-amino-4-ethylthiobenzoic acid, B. P. C. at 4 mm.; the methyl ester of 3-amino-4-npropylthiobenzoic acid, B. P. 182 C. at 6 mm.; the corresponding beta-diethylaminoethyl esters, B. P. 218-23 C. at 4 mm., and 230-4 C. at 4 mm. respectively; and the corresponding hydrochlorides, M. P. 11823 C. and -4 C., respectively.

In similar manner, using gamma-diethylclosure, as is the case in the copending application referred to, now Patent No. 2,173,827, dated September 26, 1939.

While the invention has been described in great detail in the foregoing specifications, the same is to be considered as illustrative only and not restrictive in character.

Modifications comparable to those disclosed in the copending application, as well as others will readily suggest themselves to persons skilled in this art. At the present time an isomeric series to the new compounds herein described are being subjected to experimental and clinical tests. The present disclosure is intended as a basic disclosure of basic compounds previously described and the related compounds which differ in the position of the groups in the benzene ring.

The invention claimed is:

1. An organic compound of the group consisting of esters having the formula where a: is an integer greater than unity and R, R." and R represent alkyl radicals, and acid addition compounds thereof.

2. .An organic compound having the formula para-RS-meta-NI-Iz CsHsCOO (CHzh; NR"R."', where a: is an integer greater than one and less than four and R, R" and R' represent alkyl radicals containing not more than six carbon atoms.

3. An organic compound having the formula ortho-R'S-para-N'Hz CsHsCOO (CHzh; NR"R"', Where a: is an integer greater than one and less than four and R, R." and R represent alkyl radicals containing not more than six carbon atoms.

4. Diethylaminoethyl amino-benzoate.

5. Diethylaminopropyl para-methylthio-metaamino-benzoate.

para-methylthio-meta- JOHN J. DONLEAVY. 

